Targeting CD99 in association with doxorubicin: An effective combined treatment for Ewing’s sarcoma

Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, Bologna 40136, Italy.
European Journal of Cancer (Impact Factor: 5.42). 02/2006; 42(1):91-6. DOI: 10.1016/j.ejca.2005.09.015
Source: PubMed


CD99 is a 32kDa surface glycoprotein that is involved in the migration of leukocytes, cell-cell adhesion and apoptosis of T cells and Ewing's sarcoma (ES) cells, two cell types with a high level of CD99 expression. Engagement of the molecule induces a rapid death signal that appears to be related to the level of expression of this antigen. The rapid apoptosis induced by agonistic anti-CD99 monoclonal antibodies is of clinical interest in ES, a tumour for which no new drugs have been described as clearly effective in the last 10 years. In this study, we show that an anti-CD99 monoclonal antibody can be used to advantage in association with doxorubicin. Striking effectiveness was observed against local tumours and metastases. No remarkably toxic effects of anti-CD99 monoclonal antibody were found in bone marrow against blood precursors. These results provide the necessary rationale and support for a novel modality of therapeutic intervention, which may have application in the care of patients with ES.

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Available from: Giordano Nicoletti
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    • "Furthermore, endogenous CD99 expression in EWS modulates tumor differentiation and malignancy and represents a medically relevant target molecule for the diagnosis and therapy of EWS (Rocchi et al. 2010). To this regard, it has been previously described that engagement of CD99 by agonistic murine monoclonal antibodies (mAbs) can significantly inhibit the growth of Ewing tumor cells in vitro and in vivo models by apoptotic stimulus, thus reducing the malignant potential of these cancer cells (Scotlandi et al. 2006). MAb-based therapy is the fastest growing sector of pharmaceutical biotechnology, and a number of antibody-based biopharmaceuticals have been approved for different human pathologies (Reichert 2015). "
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    ABSTRACT: Ewing's sarcoma (EWS) is the second most common primary bone tumor in pediatric patients characterized by over expression of CD99. Current management consists in extensive chemotherapy in addition to surgical resection and/or radiation. Recent improvements in treatment are still overshadowed by severe side effects such as toxicity and risk of secondary malignancies; therefore, more effective strategies are urgently needed. The goal of this work was to develop a rapid, inexpensive, and "up-scalable" process of a novel human bivalent single-chain fragment variable diabody (C7 dAbd) directed against CD99, as a new therapeutic approach for EWS. We first investigated different Escherichia coli constructs of C7 dAbd in small-scale studies. Starting from 60 % soluble fraction, we obtained a yield of 25 mg C7 dAbd per liter of bacterial culture with the construct containing pelB signal sequence. In contrast, a low recovery of C7 dAbd was achieved starting from periplasmic inclusion bodies. In order to maximize the yield of C7 dAbd, large-scale fermentation was optimized. We obtained from 75 % soluble fraction 35 mg C7 dAbd per L of cell culture grown in a synthetic media containing 3 g/L of vegetable peptone and 1 g/L of yeast extract. Furthermore, we demonstrated the better efficacy of the cell lysis by homogenization versus periplasmic extraction, in reducing endotoxin level of the C7 dAbd. For gram-scale purification, a direct aligned two-step chromatography cascade based on binding selectivity was developed. Finally, we recovered C7 dAbd with low residual process-related impurities, excellent reactivity, and apoptotic ability against EWS cells.
    Full-text · Article · Dec 2015 · Applied Microbiology and Biotechnology
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    • "HSPs are chaperone proteins that help to maintain protein stability, renature unfolded proteins, or target their degradation [117, 118]. Several of these HSP client proteins are involved in signal transduction pathways that lead to proliferation, apoptosis, or cell cycle progression in several cancers, which is precisely the case for IGF1R [119, 120]. Therefore, HSP inhibition is a therapeutic strategy to inhibit multiple receptor pathways. "
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    ABSTRACT: Rhabdomyosarcomas (RMS) are a heterogeneous group of tumors that share features of skeletal myogenesis and represent the most common pediatric soft tissue sarcoma. Even though significant advances have been achieved in RMS treatment, prognosis remains very poor for many patients. Several elements of the Insulin-like Growth Factor (IGF) pathway are involved in sarcomas, including RMS. The IGF2 ligand is highly expressed in most, if not all, RMS, and frequent overexpression of the receptor IGF1R is also found. This is confirmed here through mining expression profiling data of a large series of RMS samples. IGF signaling is implicated in the genesis, growth, proliferation, and metastasis of RMS. Blockade of this pathway is therefore a potential therapeutic strategy for the treatment of RMS. In this paper we examine the biological rationale for targeting the IGF pathway in RMS as well as the current associated preclinical and clinical experience.
    Full-text · Article · Mar 2011 · Sarcoma
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    ABSTRACT: Background Although cure rates for childhood cancer have improved from below 20% to more than 75% during the last 40 years, childhood cancer is still the number one killer amongst paediatric diseases. European paediatric cancer research also faces new challenges by the increasing number of childhood cancer survivors, some of whom experience significantly altered life-quality due to serious psychosocial and medical long-term side-effects of the intensive cancer treatment. Hence, to achieve even higher quantity and quality of cure for Europe’s children and adolescents with cancer, development of new treatment options is now required, as are intensified epidemiological investigations into health and psycho-social issues of paediatric cancer survivors on the EU-level. Methods Based on presentations and discussions at a recent meeting of leading European paediatric oncologists supported by the EC-funded science-communication project “DIRECT", this article discusses the situation of European paediatric cancer research under the EU-Framework Programmes (FPs). Results Single, partially interlinking paediatric oncological research projects received EU-funding during the last three FPs. However, given the increased budgets for health research under the FP6 and FP7 together with their goal to improve the European Research Area (ERA), relatively few of the current challenges in European paediatric oncology have been covered so far when compared to the spending for adult cancer. Conclusion Although still fragmented, current EC-funded projects in paediatric oncology would be amenable to a higher level of integration. In order to achieve a closer approach to “total cure” including all medical, psychological and social aspects, paediatric cancer should become a horizontal priority of European research funding.
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